PROJECT SUMMARY/ABSTRACT This proposal describes a research and training program that will allow Dr. Monica Campo Patino to achieve her long-term goal of becoming an independently funded translational physician-scientist in the area of Mycobacterium tuberculosis (Mtb) immunopathogenesis. Dr. Campo is a faculty member of the Division of Pulmonary and Critical Care Medicine at the University of Washington (UW) and has previous experience in immunology laboratory based techniques. She developed a comprehensive career development plan that builds on her previous training. This includes a research program focused on elucidating the role of epigenetic mechanisms such as histone deacetylation in conferring resistance to Mtb infection. In addition, Dr. Campo included didactic training in the responsible conduct of biomedical research and coursework in molecular biology, epigenetics and career advancement. This work will be conducted under the mentorship of Dr. Thomas R. Hawn, Professor of Medicine at the UW and a diverse scientific and career advisory committee. Dr. Campo will execute her project at the UW, which provides a rich academic environment as one of the top NIH- funded research institutions in the country. Dr. Campo's research focuses on discovering the cellular mechanisms of natural resistance to Mtb infection that can be targeted by new therapies. To achieve this, she leveraged a unique cohort of household contacts of TB cases of which 9% are individuals who resist Mtb infection despite being in a TB endemic area. The histone deacetylase (HDAC) gene family was found to distinguish individuals resistant to infection from those latently infected by using transcriptional profiling. Dr. Campo's preliminary data supports this finding, demonstrating that a Class 1 HDAC inhibitor controls Mtb growth in human monocytes and alveolar macrophages. HDAC inhibitors modulate immune responses in cancer and other inflammatory diseases, but their role in TB host response is unknown. This project's specific aim 1 will determine how class 1 HDACs regulate the mechanisms of innate immune resistance to Mtb by utilizing molecular, genetic and epigenetic techniques in human macrophages. Aim 2 will discover genetic variants that regulate HDAC1 expression and function in macrophages, and will establish whether HDAC1-deficient humans are resistant to Mtb infection. This study will provide new insights into the regulation of resistance to Mtb infection and could lead to a host- directed therapy that targets a specific HDAC and helps to eradicate infection or treat active TB disease.